Large interindividual variations in antipyrine metabolism may result from differences in genetic constitution, environmental factors or a combination of these. The significance of this study lies in a more specific definition of genetic factors controlling large interindividual variations in antipyrine metabolism. Although not all drugs are biotransformed by specific metabolic reactions that resemble those for antipyrine, the particular pharmacological properties of this test drug allow basic mechanisms of drug metabolism to be studied in a general way. By elucidating the specific biochemical pathways of antipyrine and other drugs with respect to individual metabolic steps where intersubject variation is under genetic control, we may more effectively understand the specific causes for interindividual variation in drug response and also be able thereby to administer drugs more safely and rationally. We shall study pedigrees at the extremes of antipyrine metabolism, both fast and slow metabolizers. These family studies should permit us to establish the mode of inheritance of the interindividual variations we observed in the 4-hydroxylation of antipyrine.